# Observational, causal relationship and shared genetic basis between cholelithiasis and gastroesophageal reflux disease: evidence from a cohort study and comprehensive genetic analysis

## TL;DR

This study finds a strong observational and genetic link between gallstones and GERD, suggesting shared causes and potential for new treatments.

## Contribution

The study identifies five shared genetic loci and three novel risk genes linking cholelithiasis and GERD.

## Key findings

- Individuals with cholelithiasis have nearly double the risk of developing GERD.
- Genetic liability to cholelithiasis causally increases the risk of GERD.
- Five novel shared genetic loci and three risk genes (SUN2, CBY1, JOSD1) were identified.

## Abstract

Cholelithiasis and gastroesophageal reflux disease (GERD) contribute to significant health concerns. We aimed to investigate the potential observational, causal, and genetic relationships between cholelithiasis and GERD.

The observational correlations were assessed based on the prospective cohort study from UK Biobank. Then, by leveraging the genome-wide summary statistics of cholelithiasis (N = 334,277) and GERD (N = 332,601), the bidirectional causal associations were evaluated using Mendelian randomization (MR) analysis. Subsequently, a series of genetic analyses was used to assess the genetic correlation, shared loci, and genes between cholelithiasis and GERD.

The prospective cohort analyses revealed a significantly increased risk of GERD in individuals with cholelithiasis (hazard ratio [HR] = 1.99; 95% confidence interval [CI], 1.89–2.10) and a higher risk of cholelithiasis among patients with GERD (HR = 2.30; 95% CI, 2.18–2.44). The MR study indicated the causal effect of genetic liability to cholelithiasis on the incidence of GERD (odds ratio [OR] = 1.08; 95% CI, 1.05–1.11) and the causal effect of genetic predicted GERD on cholelithiasis (OR = 1.15; 95% CI, 1.02–1.31). In addition, cholelithiasis and GERD exhibited a strong genetic association. Cross-trait meta-analyses identified 5 novel independent loci shared between cholelithiasis and GERD. Three shared genes, including SUN2, CBY1, and JOSD1, were further identified as novel risk genes.

The elucidation of the shared genetic basis underlying the phenotypic relationship of these 2 complex phenotypes offers new insights into the intrinsic linkage between cholelithiasis and GERD, providing a novel research direction for future therapeutic strategy and risk prediction.

Graphical Abstract